BRCA1-associated Protein 1 (BAP1) Deubiquitinase Antagonizes the Ubiquitin-mediated Activation of FoxK2 Target Genes

• DOI: 10.1074/jbc.m114.609834
• Publication Date: 2014-12-02T07:37:36Z
• Authors: Yuki Okino; Yuka Machida; Sarah Frankland-S...; Yuichi J. Machida
• Keywords: Polycomb Repressive Complex 1; 0301 basic medicine; Sequence Homology, Amino Acid; Ubiquitin; Tumor Suppressor Proteins; Molecular Sequence Data; Forkhead Transcription Factors; Chromatin; Gene Expression Regulation, Enzymologic; Recombinant Proteins; Protein Structure, Tertiary; 3. Good health; Gene Expression Regulation, Neoplastic; 03 medical and health sciences; HEK293 Cells; Neoplasms; Humans; RNA Interference; Amino Acid Sequence; Phosphorylation; Ubiquitin Thiolesterase; Glutathione Transferase; Protein Binding

BRCA1-associated protein 1 (BAP1), which is frequently mutated in cancer, functions as a deubiquitinase (DUB) for histone H2A. Although BAP1 interacts with a transcriptional regulator, HCF-1, and transcription factors FoxK1 and FoxK2, how BAP1 controls gene expression remains unclear. This study investigates the importance of BAP1 DUB activity and the interactions with FoxK2 and HCF-1 in the regulation of FoxK2 target genes. We show that FoxK2 recruits BAP1 to the target genes through the forkhead-associated domain, which interacts with Thr(P)-493 on BAP1. BAP1, in turn, recruits HCF-1, thereby forming a ternary complex in which BAP1 bridges FoxK2 and HCF-1. BAP1 represses FoxK2 target genes, and this effect requires BAP1 DUB activity but not interaction with HCF-1. Importantly, BAP1 depletion causes up-regulation of FoxK2 target genes only in the presence of the Ring1B-Bmi1 complex, an E3 ubiquitin ligase for histone H2A, indicating an antagonizing role of BAP1 against Ring1B-Bmi1. Our findings suggest that BAP1 deficiency causes increased expression of target genes in a Ring1B-Bmi1-dependent manner.